The maternal brain is more flexible and responsive at rest: effective connectivity of the parental caregiving network in postpartum mothers

The field of neuroscience has largely overlooked the impact of motherhood on brain function outside the context of responses to infant stimuli. Here, we apply spectral dynamic causal modelling (spDCM) to resting-state fMRI data to investigate differences in brain function between a group of 40 first-time mothers at 1-year postpartum and 39 age- and education-matched women who have never been pregnant. Using spDCM, we investigate the directionality (top–down vs. bottom–up) and valence (inhibition vs excitation) of functional connections between six key left hemisphere brain regions implicated in motherhood: the dorsomedial prefrontal cortex, ventromedial prefrontal cortex, posterior cingulate cortex, parahippocampal gyrus, amygdala, and nucleus accumbens. We show a selective modulation of inhibitory pathways related to differences between (1) mothers and non-mothers, (2) the interactions between group and cognitive performance and (3) group and social cognition, and (4) differences related to maternal caregiving behaviour. Across analyses, we show consistent disinhibition between cognitive and affective regions suggesting more efficient, flexible, and responsive behaviour, subserving cognitive performance, social cognition, and maternal caregiving. Together our results support the interpretation of these key regions as constituting a parental caregiving network. The nucleus accumbens and the parahippocampal gyrus emerging as ‘hub’ regions of this network, highlighting the global importance of the affective limbic network for maternal caregiving, social cognition, and cognitive performance in the postpartum period.


Spectral Dynamic Causal Modelling
Dynamic causal modelling (DCM) is a Bayesian framework that allows directed (causal) connections to be inferred between neural systems: known as effective connectivity. In resting-state data, the DCM approach is based on a deterministic model that generates cross-spectra predictions, and is referred to as spectral DCM (spDCM) 1 . We have previously applied spDCM to studies of resting-state connectivity in obesity 2 and decision-making 3 . Full details of the spDCM approach is provided in Friston et al. 1 and Voigt et al. 2 , but is described briefly here.
In order to model brain activity in the absence of external stimuli or evoked responses, the spDCM model adds a stochastic component to the classic DCM based on ordinary differential equations. Mathematically, the stochastic generative model is expressed using two equations: The neuronal state equation (S1): where x (t) is the rate of change of the neuronal states x(t), θ are unknown parameters (i.e., the effective connectivity) and v(t) (resp. e(t)) is the stochastic process -called the state noise (resp. the measurement or observation noise) -modelling the random neuronal fluctuations that drive the resting state activity. In the observation equations, φ are the unknown parameters of the (haemodynamic) observation function and u(t) represents any exogenous (or experimental) inputs that drive the hidden states -that are usually absent in resting state designs. spDCM furnishes a constrained inversion of the stochastic model by parameterising the neuronal fluctuations ( ). spDCM simplifies the generative model by replacing the original timeseries with its second-order statistic, the cross-spectra. As such, instead of estimating time-variant hidden states, spDCM estimates their temporally-invariant covariance.
The parametric empirical Bayes (PEB) framework 4 was used to test for differences in effective connectivity.
Empirical Bayes refers to the process of Bayesian model inversion or fitting of hierarchical models. In a hierarchical model, the constraints on the posterior density of model parameters at a given level is provided by the level above. The constraints are called empirical priors because they are informed by the data. PEB is a second-level model over parameters, and represents how individual within-subject connections derive from the subjects' group membership. PEB relies upon Bayesian Model Reduction (BMR) to refine the inversion of multiple models of a single dataset, or a single hierarchical model of multiple datasets. BMR can improve subject-specific parameter estimates by using group-level estimates to inform the calculation of individual DCMs from local optima.

Effect of Wellbeing
In general, the effect of wellbeing was modest across all analyses (Supplementary Figure 1). For the main effect of group, no additional connections were identified when controlling for wellbeing (Supplementary

Cognition Summary Scores
Supplementary Tables 5-8 report the principle components results for the cognition data. Supplementary Table   9 reports the means and standard deviations of the cognitive data. Please refer to Orchard

Nucleus Accumbens and Parahippocampal Gyrus: Hub Regions of the Maternal Brain
The results indicated that the nucleus accumbens and the parahippocampal gyrus are 'hub' regions of the maternal caregiving brain network. Both regions showed significant connections in every model tested: main effect of group, main effect of maternal caregiving, interaction effect of group-by-cognition, and interaction effect of group-by-social cognition. Both the nucleus accumbens and parahippocampal gyrus are part of both the ventromedial emotion regulation system 5 and the affective limbic network 6 , suggesting that the increased influence of these regions supports, and perhaps integrates, the functions of both networks.
The nucleus accumbens, part of the striatum and mesolimbic reward circuit, is considered a crucial region in the human maternal brain 7 , showing both structural and functional neural adaptations across the peripartum period. The nucleus accumbens decreases in volume up to 25% across pregnancy 8 , and at twomonths postpartum 9 , with greater volume reductions associated with increased activation in response to infant stimuli 10 . The striatum also shows grey matter volume increases later in the postpartum period. Specifically, consistent increases in grey matter volume were found in the caudate 11,12 , putamen 11 , nucleus accumbens 13 , and pallidum 11 . Studies of resting state functional connectivity have also highlighted the role of the nucleus accumbens in sensitive maternal caregiving behaviours 14, 15 . Increased connectivity between the nucleus accumbens and the amygdala is associated with a mother's ability to scaffold appropriate interactions with her child 14 . Positive maternal caregiving behaviours were also related to functional connectivity between the nucleus accumbens and the dorsomedial prefrontal cortex 15 , and activation of the nucleus accumbens is correlated with increased oxytocin levels 15 . Our results, alongside the extant literature highlight the importance of the nucleus accumbens in the global functioning of the maternal brain. Our results emphasise the influence of the nucleus accumbens for maternal cognition, and social cognition, and that the increased inhibitory influence of the nucleus accumbens may play a central role in maternal caregiving.
The parahippocampal gyrus also undergoes structural plasticity in motherhood, with grey matter changes across pregnancy 8 , the postpartum period 11 , and in late-life 16 . The parahippocampal gyrus is involved in memory consolidation and cohesion 17 and mediates cortico-hippocampal communication 18 . Altered parahippocampal structure and function is potentially related to changes in maternal cognition across pregnancy 19 . However, the involvement of the parahippocampal gyrus appears to extend beyond the cognitive domain. The parahippocampal gyrus is implicated across many studies of maternal brain function and sensitive caregiving 8,11,16 , suggesting this region has a broader role in maternal caregiving. A recent metaanalysis has highlighted the parahippocampal gyrus as one of only six brain regions that show consistent activation in response to visual stimuli of a mother's own child, compared to an unknown control child 20 .
Studies of resting state functional connectivity show disrupted connectivity between the parahippocampal gyrus, and the posterior cingulate cortex 21 , amygdala 21 , and dorsomedial prefrontal cortex 22 . Taken together, the parahippocampal gyrus is a key region of the maternal brain, which deserves increased attention in future studies.

Social Cognition
Compared to non-mothers, mothers had significantly higher scores on measures of social cognition (theory of mind, and empathy; Supplementary Tables 1; 5). Social cognition abilities contribute to successful social interactions and are important for human survival and successful maternal behaviours 23 . Motherhood requires a heightened focus on infant-related responsibilities, and for a mother to be more in tune with the thoughts, feelings, and needs of their children, especially pre-verbal infants, where infant needs must be interpreted without verbal communication 24 . This result is consistent with superior social cognition found in pregnant women, where mothers show improved ability to encode emotional faces during late pregnancy, compared to early pregnancy 25 , and increased facial recognition compared to non-pregnant women 26 .
Interestingly, both the Reading the Mind in the Films Task and the Toronto Empathy Questionnaire are designed to assess social cognition in adults, are not specific to motherhood or the peripartum period, and do not contain questions or items about caring for children 27,28 . These observations support the interpretation that mothers' superior social cognition performance may generalise beyond the context of childcare-related skills and behaviours, to abilities that may benefit mothers in their social interactions with other adults.

Selective Modulation of Inhibitory Connectivity in Motherhood
Our findings suggest a selective modulation of inhibitory pathways in motherhood. Inhibition in a cortical hierarchy serves to maintain efficient neural signalling by modulation of the primary inhibitory neurotransmitter, gamma-aminobutyric acid (GABA) 40,68 . In pregnancy and the postpartum period, GABAergic activation is modulated by fluctuating concentrations of neurosteroids, such as allopregnanolone (a metabolite of progesterone). Allopregnanolone acts at the GABA-A receptor to increase inhibition 69,70 , and GABA-A receptor density and sensitivity are flexibly upregulated and downregulated to maintain an ideal homeostatic level of inhibition 68,69 (i.e., at times of high allopregnanolone, receptor density and sensitivity are down-regulated, and vice versa). Allopregnanolone concentrations fluctuate across the peripartum period, with high levels in late pregnancy, followed by a rapid decline at parturition. Allopregnanolone levels remain low throughout the postpartum period until the return of menstruation, and cessation of breastfeeding.
Weaning therefore represents an increase in the concentration of allopregnanolone and a period of GABAergic plasticity 71 . Our observed differences in inhibitory connectivity in mothers at one-year postpartum may reflect the reorganisation of the GABAergic system at this time 30 , providing a potential mechanism for our results.
Plasticity of the GABAergic system across the peripartum is related to maternal behaviour, and dysregulation of GABAergic signalling in rodents results in deficits in maternal care, and increased symptoms of anxiety and depression 68 . Our interpretation of the selective modulation of inhibitory connectivity would be strengthened with the addition of hormonal data, which was not collected from this sample. Therefore, it is not possible to assert that the differences we observed are related to levels of allopregnanolone. Future research should investigate the relationships between fluctuating hormone levels and inhibitory connectivity across the peripartum period.